Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Cardiovasc Diabetol. 2010 Aug 24;9:43. doi: 10.1186/1475-2840-9-43.
The mechanisms responsible for the cardiovascular mortality in type I diabetes (DM) have not been defined completely. We have shown in conscious dogs with DM that: 1) baseline coronary blood flow (CBF) was significantly decreased, 2) endothelium-dependent (ACh) coronary vasodilation was impaired, and 3) reflex cholinergic NO-dependent coronary vasodilation was selectively depressed. The most likely mechanism responsible for the depressed reflex cholinergic NO-dependent coronary vasodilation was the decreased bioactivity of NO from the vascular endothelium. The goal of this study was to investigate changes in cardiac gene expression in a canine model of alloxan-induced type 1 diabetes.
Mongrel dogs were chronically instrumented and the dogs were divided into two groups: one normal and the other diabetic. In the diabetic group, the dogs were injected with alloxan monohydrate (40-60 mg/kg iv) over 1 min. The global changes in cardiac gene expression in dogs with alloxan-induced diabetes were studied using Affymetrix Canine Array. Cardiac RNA was extracted from the control and DM (n = 4).
The array data revealed that 797 genes were differentially expressed (P < 0.01; fold change of at least ±2). 150 genes were expressed at significantly greater levels in diabetic dogs and 647 were significantly reduced. There was no change in eNOS mRNA. There was up regulation of some components of the NADPH oxidase subunits (gp91 by 2.2 fold, P < 0.03), and down-regulation of SOD1 (3 fold, P < 0.001) and decrease (4 - 40 fold) in a large number of genes encoding mitochondrial enzymes. In addition, there was down-regulation of Ca2+ cycling genes (ryanodine receptor; SERCA2 Calcium ATPase), structural proteins (actin alpha). Of particular interests are genes involved in glutathione metabolism (glutathione peroxidase 1, glutathione reductase and glutathione S-transferase), which were markedly down regulated.
our findings suggest that type I diabetes might have a direct effect on the heart by impairing NO bioavailability through oxidative stress and perhaps lipid peroxidases.
导致 1 型糖尿病（DM）心血管死亡率的机制尚未完全明确。我们已经在患有 DM 的清醒犬中证明：1）基础冠状动脉血流量（CBF）明显降低，2）内皮依赖性（ACh）冠状动脉舒张受损，3）反射性胆碱能一氧化氮依赖性冠状动脉舒张选择性降低。导致反射性胆碱能一氧化氮依赖性冠状动脉舒张降低的最可能机制是血管内皮产生的 NO 生物活性降低。本研究的目的是研究犬阿霉素诱导 1 型糖尿病模型中心脏基因表达的变化。
慢性植入杂种犬，将犬分为两组：一组正常，另一组糖尿病。在糖尿病组中，将犬在 1 分钟内静脉注射阿霉素一水合物（40-60mg/kg）。使用 Affymetrix 犬阵列研究阿霉素诱导糖尿病犬心脏基因表达的整体变化。从对照组和 DM 中提取心脏 RNA（n=4）。
数组数据显示，797 个基因差异表达（P<0.01；至少±2 倍变化）。150 个基因在糖尿病犬中表达水平显著升高，647 个基因显著降低。eNOS mRNA 无变化。NADPH 氧化酶亚基的一些成分上调（gp91 上调 2.2 倍，P<0.03），SOD1 下调（3 倍，P<0.001），大量编码线粒体酶的基因下调（4-40 倍）。此外，钙循环基因（兰尼碱受体；肌浆网 Ca2+-ATP 酶）、结构蛋白（肌动蛋白α）下调。特别值得关注的是参与谷胱甘肽代谢的基因（谷胱甘肽过氧化物酶 1、谷胱甘肽还原酶和谷胱甘肽 S-转移酶），这些基因明显下调。
我们的发现表明，1 型糖尿病可能通过氧化应激和脂质过氧化物酶损害 NO 生物利用度对心脏产生直接影响。
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